EP2551671A2 - Dispositif d'immuno-essai possédant une électrode de référence immunologique - Google Patents

Dispositif d'immuno-essai possédant une électrode de référence immunologique Download PDF

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Publication number
EP2551671A2
EP2551671A2 EP12179659A EP12179659A EP2551671A2 EP 2551671 A2 EP2551671 A2 EP 2551671A2 EP 12179659 A EP12179659 A EP 12179659A EP 12179659 A EP12179659 A EP 12179659A EP 2551671 A2 EP2551671 A2 EP 2551671A2
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EP
European Patent Office
Prior art keywords
sample
immunosensor
sensor
blood
conduit
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Granted
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EP12179659A
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German (de)
English (en)
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EP2551671B1 (fr
EP2551671A3 (fr
Inventor
Cary James Miller
John Lewis Emerson Campbell
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Abbott Point of Care Inc
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Abbott Point of Care Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G01N33/5438—Electrodes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/807—Apparatus included in process claim, e.g. physical support structures
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation

Definitions

  • US 5,081,063 discloses the use of permselective layers for electrochemical sensors and the use of film-forming latexes for immobilization of bioactive molecules, incorporated here by reference.
  • the use of poly(vinyl alcohol) (PVA) in sensor manufacture is described in US 6,030,827 incorporated here by reference.
  • Vikholm (US 2003/0059954A1 ) teaches antibodies directly attached to a surface with a biomolecule repellant coating, e.g. PVA, the surface in the gaps between antibodies, and Johansson (US 5,656,504 ) teaches a solid phase, e.g. PVA, with antibodies immobilized thereon.
  • US 6,030,827 and 6,379,883 teach methods for patterning poly(vinylalcohol) layers and are incorporated by reference in their entirety
  • sealing element 200 is positioned within a few thousandths of an inch above the surface of the tape gasket 21 of figure 3 .
  • Carboxylate-modified latex microparticles supplied by Bangs Laboratories Inc. or Seradyn Microparticles Inc. coated with anti-cTnI and anti-HSA are both prepared by the same method.
  • the particles are first buffer exchanged by centrifugation, followed by addition of the antibody, which is allowed to passively adsorb onto the particles.
  • the carboxyl groups on the particles are then activated with EDAC in MES buffer at pH 6.2, to form amide bonds to the antibodies. Any bead aggregates are removed by centrifugation and the finished beads are stored frozen.
  • Coated beads were prepared using covalent attachment from a mixture comprising 7 mg of anti-HSA and 100 mg of beads. Using this preparation a droplet of about 0.4 nL, comprising about 1% solids in deionized water, was microdispensed (using the method and apparatus of US 5,554,339 , incorporated here by reference) onto a photo-patterned porous polyvinyl alcohol permselective layer covering sensor 96, and allowed to dry. The dried particles adhered to the porous layer and substantially prevented their dissolution in the blood sample or the washing fluid.
  • HSA anti-human serum albumin
  • the currents associated with oxidation of p-aminophenol at immunosensor 94 and immuno-reference sensor 96 arising from the activity of ALP, are recorded by the analyzer.
  • the potentials at the immunosensor and immuno-reference sensor are poised at the same value with respect to a silver-silver chloride reference electrode.
  • the analyzer subtracts the signal of the immune-reference sensor from that of the immunosensor according to equation (4). Where there is a characteristic constant offset between the two sensors, this also is subtracted.
  • the cartridge design provides dry reagent that yields about 4-5 billion enzyme conjugate molecules dissolved into about a 10 uL blood sample. At the end of the binding and wash steps the number of enzyme molecules at the sensor is about 70,000. In experiments with the preferred embodiment there were, on average, about 200,000 (+/- about 150,000) enzyme molecules on the immunosensor and the reference immunosensor as non-specifically bound background. Using a differential measurement with the immuno-reference sensor, about 65% of the uncertainty was removed, significantly improving the performance of the assay. While other embodiments may have other degrees of improvement, the basis for the overall improvement in assay performance remains.
  • the level of signal at an immunosensor depends on the extent of washing. For example, longer washing with more fluid/air segment transitions can give a lower signal level due to a portion of the specifically bound conjugate being washed away. While this may be a relatively small effect, e.g. less than 5%, correction can improve the overall performance of the assay. Correction may be achieved based on the relative signals at the sensors, or in conjunction with a conductivity sensor located in the conduit adjacent to the sensors, acting as a sensor for detecting and counting the number of air segment/fluid transitions. This provides the input for an algorithmic correction means embedded in the analyzer.
  • the reference immunosensor with an endogenous protein e.g. HSA
  • an immuno-reference sensor coated with antibody to an exogenous protein e.g. bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • the step of dissolving a portion of the BSA in the sample, provided as an additional reagent, prior to contacting the sensors is needed.
  • This dissolution step can be done with BSA as a dry reagent in the sample holding chamber of the cartridge, or in an external collection device, e.g. a BSA-coated syringe.
  • This approach offers certain advantages, for example the protein may be selected for surface charge, specific surface groups, degree of glycosylation and the like. These properties may not necessarily be present in the available selection of endogenous proteins.
  • albumin from the sample rapidly coats the beads as described above. Once they are coated with a layer of native albumin the leukocytes do not recognize the beads as an opsonized surface, resulting in the observed effect of limiting the leukocytes' ability to cause the bias.
  • salt is added to the sample by coating the wall of the sample holding chamber with a mixture of NaCl, lactitol and DEAE dextran at pH 7.4 using Tris at about 5% total solids.
  • Gelatin, cellulose and PVA can also be used as the support matrix, but the dissolution rate is not quite as fast as the lactitol and DEAE mixture.
  • Sample hematocrit values may vary widely between immunoassays performed on whole-blood and this can affect the results. A way to eliminate this effect has been discovered.
  • the reagents that form the immuno-complex dissolve into the plasma fraction only, not into the cells, which are predominantly erythrocytes. Erythrocytes typically occupy about 40% of a blood sample, though this can vary widely between patients.
  • the percentage of the blood sample volume occupied by these cells is called the hematocrit value. For a given volume of blood, the higher the hematocrit value the less plasma volume is available for a given amount of reagent to dissolve in; thus, the effective reagent concentration is higher.
  • the signal generated in the assay increases with increasing hematocrit.
  • This effect can be corrected for by measuring the hematocrit of the sample during the assay.
  • the analyte concentration can then be reported so as to agree with typical laboratory values obtained from spun samples, i.e. serum or plasma samples where hematocrit equals zero.
  • hematocrit is an inverse function of conductivity, assuming a normal concentration of current-carrying ions in the sample.
  • standard curves are created using samples with independently determined analyte concentrations and hematocrit values.
  • an algorithm can be developed and embedded into the analyzer and used for real samples, whereby the conductivity measured at an adjacent sensor in the cartridge is used to estimate hematocrit and correct the signal from the immunosensor. For example, the algorithm may simply subtract a percentage of the signal per hematocrit unit in order to correct the result to a hematocrit of zero, i.e. plasma.
  • a cartridge of the present invention has the advantage that the sample and a second fluid can contact the sensor array at different times during an assay sequence.
  • the sample and second fluid may also be independently amended with other reagents or compounds present initially as dry coatings within the respective conduits. Controlled motion of the liquids within the cartridge further permits more than one substance to be amended into each liquid whenever the sample or fluid is moved to a new region of the conduit. In this way, provision is made for multiple amendments to each fluid, greatly extending the complexity of automated assays that can be performed, and therefore enhancing the utility of the present invention.
  • Restrictions within the conduits serve several purposes in the present invention.
  • a capillary stop located between the sample chamber and first conduit is used to prevent displacement of the sample in the holding chamber until sufficient pressure is applied to overcome the resistance of the capillary stop.
  • a restriction within the second conduit is used to divert wash fluid along an alternative pathway towards the waste chamber when the fluid reaches the constriction. Small holes in the gasket, together with a hydrophobic coating, are provided to prevent flow from the first conduit to the second conduit until sufficient pressure is applied.
  • One embodiment of the invention therefore, provides a single-use cartridge with a sample-holding chamber connected to a first conduit which contains an analyte sensor or array of analyte sensors.
  • a second conduit partly containing a fluid, is connected to the first conduit and air segments can be introduced into the fluid in the second conduit in order to segment it.
  • Pump means are provided to displace the sample within the first conduit, and displaces fluid from the second conduit into the first conduit.
  • the sensor or sensors can be contacted first by a sample and then by a second fluid.
  • the sample is amended with an antibody-enzyme conjugate that binds to the analyte of interest within the sample before the amended sample contacts the sensor. Binding reactions in the sample produce an analyte / antibody-enzyme complex.
  • the sensor comprises an immobilized antibody to the analyte, attached close to an electrode surface. Upon contacting the sensor, the analyte / antibody-enzyme complex binds to the immobilized antibody near the electrode surface.
  • the enzyme of the antibody-enzyme complex is advantageously capable of converting a substrate, provided in the fluid, to produce an electrochemically active species.
  • This active species is produced close to the electrode and provides either a current from a redox reaction at the electrode when a suitable potential is applied (amperometric operation).
  • a suitable potential is applied (amperometric operation).
  • the electroactive species is an ion, it can be measured potentiometrically. In amperometric measurements the potential may either be fixed during the measurement, or varied according to a predetermined waveform.
  • the immunosensor is advantageously microfabricated from a base sensor of an unreactive metal such as gold, platinum or iridium, and a porous permselective layer which is overlaid with a bioactive layer attached to a microparticle, for example latex particles.
  • the microparticles are dispensed onto the porous layer covering the electrode surface, forming an adhered, porous bioactive layer.
  • the bioactive layer has the property of binding specifically to the analyte of interest, or of manifesting a detectable change when the analyte is present, and is most preferably an immobilized antibody directed against the analyte.
  • a second fluid which contains an electroinactive substrate for the enzyme, is used to rinse the immunosensor substantially free of unbound antibody-enzyme conjugate, and the electrical response of the immunosensor electrode is recorded and analyzed for the presence, or amount of, the analyte of interest.
  • the cartridge may contain a plurality of immunosensors and reagents.
  • the assay can be run in a system where the sample and other fluids and reagents are thermostated at a given temperature, e.g. 37oC.
  • the assay may be run at ambient temperature, without any correction, or with correction to a standardized temperature based on measurement of the ambient value.
  • a battery-powered analyzer is used and it is generally desirable to conserve battery life, it may be desirable to heat only the capture location of the assay device or cartridge.
  • the ambient temperature will have an effect on the cooling of the sample if it enters regions adjacent to the capture location.
  • the analyte capture and signal generation steps may have small temperature dependencies and so it is desirable that the net current is corrected to an ambient temperature (ATemp), e.g. 23°C, for example in accordance with equation 6.
  • ATemp ambient temperature
  • the value of the (per degree) coefficient c1 is generally not specific to a given lot of manufactured cartridges, but can be generalized to a given cartridge manufacturing process. It generally has a relatively small value, e.g. 1 to 3%. One skilled in the art will recognize that this can be determined from temperature-dependence experiments.
  • iTCorr iNet * 1 + c ⁇ 1 * ATemp - TempC
  • the conductivity correction function can be determined experimentally, where a whole blood sample is spiked with a known amount of TnI, and manipulated through centrifugation and alteration of the plasma fraction so as to yield an array of standardized samples having the same plasma concentration of analyte but Hct varying from 0 to approximately 65 percent. Performing an immunoassay of these samples in the cartridges affords collection of a set of signals as a function of conductivity. Normalization of this function, so that plasma is associated with a signal generation factor of unity, affords the conductivity correction function. This may take one of several mathematical forms, including four point logistical functions and the quadratic form shown in equation 7.
  • Equation 7 the actual coefficients in Equation 7 will depend on the reagent components and have some sensitivity to the means by which the immunoassay is carried out, e.g. the capture time.
  • the value of fCond is limited by equations 8 and 9.
  • equation 8 if the measured conductivity is below a value expected for a Hct value of for example 15 percent, then the sample is treated as a plasma sample and the correction factor is set to 5.
  • the analyzer may set c6 to zero, whereas other digits may code for different coefficients or select a kinetic model to be used, e.g. an immunoassay model formulated by analogy to the well-known Michaelis-Menton enzyme kinetics, as in equation 11.
  • the cover further comprises two paddles 6, 7, that are moveable relative to the body of the cover, and which are attached to it by flexible hinge regions 5, 10.
  • paddle 6 exerts a force upon an air bladder comprised of cavity 43, which is covered by thin-film gasket 21, to displace fluids within conduits of the cartridge.
  • paddle 7 exerts a force upon the gasket 21, which can deform because of slits 22 cut therein.
  • the cartridge is adapted for insertion into a reading apparatus, and therefore has a plurality of mechanical and electrical connections for this purpose. It should also be apparent that manual operation of the cartridge is possible.
  • thin-film gasket 21 comprises various holes and slits to facilitate transfer of fluid between conduits within the base and the cover, and to allow the gasket to deform under pressure where necessary.
  • hole 24 permits fluid to flow from conduit 11 into waste chamber 44;
  • hole 25 comprises a capillary stop between conduits 34 and 11;
  • hole 26 permits air to flow between recess 18 and conduit 40;
  • hole 27 provides for air movement between recess 17 and conduit 34;
  • hole 28 permits fluid to flow from conduit 19 to waste chamber 44 via optional closeable valve 41.
  • Holes 30 and 33 permit the plurality of electrodes that are housed within cutaways 35 and 37, respectively, to contact fluid within conduit 15.
  • cutaway 37 houses a ground electrode, and/or a counter-reference electrode
  • cutaway 35 houses at least one analyte sensor and, optionally, a conductimetric sensor.
  • This arrangement is therefore one possible embodiment of a metering means for delivering a metered amount of an unmetered sample into the conduits of the cartridge.
  • a waste chamber is provided, 44, for sample and/or fluid that is expelled from the conduit, to prevent contamination of the outside surfaces of the cartridge.
  • a vent connecting the waste chamber to the external atmosphere is also provided, 45.
  • FIG. 5 a schematic diagram of the features of a cartridge and components is provided, wherein 51-57 are portions of the conduits and sample chamber that can optionally be coated with dry reagents to amend a sample or fluid.
  • the sample or fluid is passed at least once over the dry reagent to dissolve it.
  • Reagents used to amend samples or fluid within the cartridge include antibody-enzyme conjugates, or blocking agents that prevent either specific or non-specific binding reactions among assay compounds.
  • a surface coating that is not soluble but helps prevent non-specific adsorption of assay components to the inner surfaces of the cartridges can also be provided.
  • the closeable valve is a mechanical valve.
  • a latex diaphragm is placed in the bottom of the air bladder on top of a specially constructed well.
  • the well contains two openings which fluidically connect the air vent to the sample conduit.
  • the analyzer plunger pushes to the bottom of the air bladder, it presses on this latex diaphragm which is adhesive backed and seals the connection between the two holes. This blocks the sample's air vent, locking the sample in place.
  • pump means 3 includes all methods by which one or more segments are inserted into the second conduit, such as a pneumatic means for displacing air from an air sac, a dry chemical that produces a gas when dissolved, or a plurality of electrolysis electrodes operably connected to a current source.
  • the segment is produced using a mechanical segment generating diaphragm that may have more than one air bladder or chamber.
  • Substrates such as p-aminophenol species, can be chosen such that the E 1 ⁇ 2 of the substrate and product differ substantially.
  • the voltammetric half-wave potential (E 1 ⁇ 2) of the substrate is substantially higher (more positive) than that of the product.
  • the product can be selectively electrochemically measured in the presence of the substrate.
  • the size and spacing of the electrode play an important role in determining the sensitivity and background signal.
  • the important parameters in the grid are the percentage of exposed metal and the spacing between the active electrodes.
  • the position of the electrode can be directly underneath the antibody capture region or offset from the capture region by a controlled distance.
  • the actual amperometric signal of the electrodes depends on the positioning of the sensors relative to the antibody capture site and the motion of the fluid during the analysis. A current at the electrode is recorded that depends upon the amount of electroactive product in the vicinity of the sensor.
  • the detection of alkaline phosphatase activity in this example relies on a measurement of the 4-aminophenol oxidation current. This is achieved at a potential of about +60 mV versus the Ag/AgCl ground chip.
  • the exact form of detection used depends on the sensor configuration, In one version of the sensor, the array of gold micro electrodes is located directly beneath the antibody capture region. When the analysis fluid is pulled over this sensor, enzyme located on the capture site converts the 4-aminophenylphosphate to 4-aminophenol in an enzyme limited reaction.
  • the concentration of the 4-aminophenylphosphate is selected to be in excess, e.g., 10 times the Km value.
  • the enzyme conjugated to an antibody or other analyte-binding molecule is urease, and the substrate is urea.
  • Ammonium ions produced by the hydrolysis of urea are detected in this embodiment by the use of an ammonium sensitive electrode.
  • Ammonium-specific electrodes are well-known to those of skill in the art.
  • a suitable microfabricated ammonium ion-selective electrode is disclosed in U.S. 5,200,051 , incorporated herein by reference.
  • Other enzymes that react with a substrate to produce an ion are known in the art, as are other ion sensors for use therewith. For example, phosphate produced from an alkaline phosphatase substrate can be detected at a phosphate ion-selective electrode.
  • a biolayer means a porous layer comprising on its surface a sufficient amount of a molecule 84 that can either bind to an analyte of interest, or respond to the presence of such analyte by producing a change that is capable of measurement.
  • a permselective screening layer may be interposed between the electrode and the biolayer to screen electrochemical interferents as described in US 5,200,051 .
  • a biolayer is constructed from latex beads of specific diameter in the range of about 0.001 to 50 microns.
  • the beads are modified by covalent attachment of any suitable molecule consistent with the above definition of a biolayer.
  • Many methods of attachment exist in the art, including providing amine reactive N-hydroxysuccinimide ester groups for the facile coupling of lysine or N-terminal amine groups of proteins.
  • the biomolecule is chosen from among ionophores, cofactors, polypeptides, proteins, glycopeptides, enzymes, immunoglobulins, antibodies, antigens, lectins, neurochemical receptors, oligonucleotides, polynucleotides, DNA, RNA, or suitable mixtures.
  • the biomolecule is an antibody selected to bind one or more of human chorionic gonadotrophin, troponin I, troponin T, troponin C, a troponin complex, creatine kinase, creatine kinase subunit M, creatine kinase subunit B, myoglobin, myosin light chain, or modified fragments of these.
  • modified fragments are generated by oxidation, reduction, deletion, addition or modification of at least one amino acid, including chemical modification with a natural moiety or with a synthetic moiety.
  • the biomolecule binds to the analyte specifically and has an affinity constant for binding analyte ligand of about 10 7 to 10 15 M -1 .
  • the present invention also envisages embodiments in which the biolayer is coated upon particles that are mobile.
  • the cartridge can contain mobile microparticles capable of interacting with an analyte, for example magnetic particles that are localized to an amperometric electrode subsequent to a capture step, whereby magnetic forces are used to concentrate the particles at the electrode for measurement.
  • mobile microparticles in the present invention are that their motion in the sample or fluid accelerates binding reactions, making the capture step of the assay faster.
  • a porous filter is used to trap the beads at the electrode.
  • FIG. 9 there is illustrated a mask design for several electrodes upon a single substrate.
  • independent electrodes and leads can be deposited.
  • a plurality of immunosensors, 94 and 96, and conductimetric sensors, 90 and 92 are provided in a compact area at low cost, together with their respective connecting pads, 91, 93, 95, and 97, for effecting electrical connection to the reading apparatus.
  • a very large array of sensors can be assembled in this way, each sensitive to a different analyte or acting as a control sensor or reference immunosensor.
  • immunosensors are prepared as follows. Silicon wafers are thermally oxidized to form approximately a 1 micron insulating oxide layer. A titanium/tungsten layer is sputtered onto the oxide layer to a preferable thickness of between 100-1000 Angstroms, followed by a layer of gold that is most preferably 800 Angstroms thick. Next, a photoresist is spun onto the wafer and is dried and baked appropriately. The surface is then exposed using a contact mask, such as a mask corresponding to that illustrated in FIG. 9 . The latent image is developed, and the wafer is exposed to a gold-etchant.
  • the patterned gold layer is coated with a photodefinable polyimide, suitably baked, exposed using a contact mask, developed, cleaned in an O 2 plasma, and preferably imidized at 350 °C for 5 hours.
  • An optional metallization of the back side of the wafer may be performed to act as a resistive heating element, where the immunosensor is to be used in a thermostatted format.
  • the surface is then printed with antibody-coated particles. Droplets, preferably of about 20 nL volume and containing 1% solid content in deionized water, are deposited onto the sensor region and are dried in place by air drying.
  • an antibody stabilization reagent supplied by SurModica Corp. or AET Ltd
  • the signal at the electrode is augmented by enzymatic regeneration of the electroactive species in the vicinity of the electrode.
  • a phosphorylated ferrocene is used as the substrate for alkaline phosphatase attached to the antibody. Hydrolysis yields a ferrocene product, which is oxidized and detected at the electrode.
  • glucose oxidase enzyme and glucose are used to re-reduce the electrochemically oxidized ferrocene, with a consequent increase in the current and detection sensitivity.
  • an electrode 130 oxidizes or reduces the electroactive product 132 of alkaline phosphatase immobilized as a complex 131 on or close to the electrode surface.
  • the electroactive species 132 is regenerated from the product 133 by the catalytic action of enzyme 134. This cycling reaction increases the concentration of electroactive species 132 in proximity to the electrode surface 130, and thereby increases the current recorded at the electrode.
  • FIG. 11 there is shown dose-response results obtained using HCG and an HCG-responsive amperometric immunosensor. Amounts of HCG equivalent to 0 to 50 miU/mL are allowed to bind to the immobilized antibody attached to the electrode, as in FIG. 10 . Referring now to FIG. 12 , good linearity, and 121, of the response of the peak sensor current with increasing HCG is found. Thus, it is demonstrated that this embodiment can precisely and rapidly quantify HCG in a sample.
  • a pump means applies pressure to air-bladder 43, forcing air through conduit 40, through cutaways 17 and 18 , and into conduit 34 at a predetermined location 27.
  • Capillary stop 25 and location 27 delimit a metered portion of the original sample. While the sample is within sample chamber 34, it is optionally amended with a compound or compounds present initially as a dry coating on the inner surface of the chamber. The metered portion of the sample is then expelled through the capillary stop by air pressure produced within air bladder 43. The sample passes into conduit 15 and into contact with the analyte sensor or sensors located within cutaway 35 .
  • the sample is amended prior to arriving at the sensor by, for example, an enzyme-antibody conjugate.
  • An antibody that binds the analyte of interest is covalently attached to an enzyme that can generate a redox active substance close to an amperometric electrode.
  • the enzyme may be alkaline phosphatase, which hydrolyzes certain organophosphate compounds, such as derivatives of p -aminophenol that liberate redox-active compounds when hydrolyzed.
  • any enzyme capable of producing, destroying, or altering any compound that may be detected by a sensor may be employed in conjunction with a matching sensor.
  • antibody-urease conjugate may be used together with an ammonium sensor.
  • the enzyme-antibody conjugate or conjugates amends the sample and binds to the analyte of interest.
  • the immunosensor can comprise immobilized antibody that binds to an analyte of interest.
  • the analyte of interest binds to the sensor, together with antibody-enzyme conjugate to which it is attached.
  • the sample containing the analyte is optionally passed repeatedly over the sensor in an oscillatory motion.
  • an oscillation frequency of between about 0.2 and 2 Hz is used, most preferably 0.7 Hz.
  • enzyme is brought into close proximity to the amperometric electrode surface in proportion to the amount of analyte present in the sample.
  • the sample is ejected by further pressure applied to air bladder 43, and the sample passes to waste chamber 44.
  • Extraneous material includes any material other than specifically bound analyte or analyte / antibody-enzyme conjugate complex.
  • the rinsing is not sufficiently protracted or vigorous as to promote dissociation of specifically bound analyte or analyte / antibody-enzyme conjugate complex from the sensor.
  • a second advantage of introducing air segments into the fluid is to segment the fluid. For example, after a first segment of the fluid is used to rinse a sensor, a second segment is then placed over the sensor with minimal mixing of the two segments. This feature further reduces background signal from the sensor by more efficiently removing unbound antibody-enzyme conjugate. After the front edge washing, the analysis fluid is pulled slowly until the first air segment is detected at a conductivity sensor. This segment is extremely effective at clearing the sample-contaminated fluid which was mixed in with the first analysis fluid sample.
  • a new portion of fluid is placed over the sensors, and the current or potential, as appropriate to the mode of operation, is recorded as a function of time.
  • time zero 0
  • the cartridge reading device makes electrical contact with the sensors through pads 91, 93, 95, and 97, and performs certain diagnostic tests. Insertion of the cartridge perforates the foil pouch introducing fluid into the second conduit as previously described.
  • the diagnostic tests determine whether fluid or sample is present in the conduits using the conductivity electrodes; determine whether electrical short circuits are present in the electrodes; and ensure that the sensor and ground electrodes are thermally equilibrated to, preferably, 37 °C prior to the analyte determination.
  • a metered portion of the sample preferably between 4 and 200 ⁇ l, more preferably between 4 and 20 ⁇ l, and most preferably 7 ⁇ l, is used to contact the sensor as described in EXAMPLE 2.
  • the edges defining the forward and trailing edges of the sample are reciprocally moved over the sensor region at a frequency that is preferably between 0.2 to 2.0 Hz, and is most preferably 0.7 Hz.
  • the enzyme-antibody conjugate dissolves within the sample, as previously described.
  • the amount of enzyme-antibody conjugate that is coated onto the conduit is selected to yield a concentration when dissolved that is preferably higher than the highest anticipated HCG concentration, and is most preferably six times higher than the highest anticipated HCG concentration in the sample.
  • the sample is moved into the waste chamber via closeable valve 41, wetting the closeable valve and causing it to close as previously described.
  • the seal created by the closing of the valve permits the first pump means to be used to control motion of fluid from conduit 11 to conduit 15.
  • the analyzer plunger retracts from the flexible diaphragm of the pump mean creating a partial vacuum in the sensor conduit. This forces the analysis fluid through the small hole in the tape gasket 31 and into a short transecting conduit in the base, 13, 14. The analysis fluid is pulled further and the front edge of the analysis fluid is oscillated across the surface of the sensor chip in order to shear the sample near the walls of the conduit.
  • the efficiency of the wash is optimally further enhanced by introduction into the fluid of one or more segments that segment the fluid within the conduit as previously described.
  • the air segment may be introduced by either active or passive means.
  • FIG. 14 there is illustrated the construction of a specific means for passively introducing an air segment into said fluid.
  • recess 140 comprising a tapered portion 141 and a cylindrical portion that are connected.
  • the tapered portion is in fluid connection with a hole 142 of similar diameter in the tape gasket ( FIG. 3 ) that separates the base ( FIG. 4 ) and cover ( FIGS 1 and 2 ) of the assembled immunosensor cartridge.
  • the recess contains an absorbent material that, upon contact with fluid, withdraws a small quantity of fluid from a conduit thereby passively introducing an air segment into the conduit.
  • the volume of the recess and the amount and type of material within it may be adjusted to control the size of the air segment introduced.
  • Specific materials include, but are not limited to, glass filter, a laminate comprising a 3 micron Versapor filter bonded by sucrose to a 60% viscose chiffon layer.
  • Fluid is forcibly moved towards sensor chip by the partial vacuum generated by reducing the mechanical pressure exerted upon paddle 6, causing the "T" region of the sensor channel in the vicinity of the transecting conduit to fill with analysis fluid.
  • the T region of the sensor channel optionally has a higher channel height resulting a meniscus with a smaller radius of curvature.
  • the conduit height is optionally smaller.
  • the analysis fluid passively flows from the T region towards this low conduit height region washing the conduit walls. This passive leak allows further effective washing of the T region using a minimal volume of fluid.
  • the fluid located within the second conduit contains a substrate for the enzyme.
  • amendment of the fluid using dried substrate within the second conduit may be used.
  • At least one sensor reading of a sample is made by rapidly placing over the sensor a fresh portion of fluid containing a substrate for the enzyme. Rapid displacement both rinses away product previously formed, and provides now substrate to the electrode. Repetitive signals are averaged to produce a measurement of higher precision, and also to obtain a better statistical average of the baseline, represented by the current immediately following replacement of the solution over the sensor.
  • Cartridge 150 comprises a base and a top portion, preferably constructed of a plastic. The two portions are connected by a thin, adhesive gasket or thin pliable film.
  • the assembled cartridge comprises a sample chamber 151 into which a sample containing an analyte of interest is introduced via a sample inlet 152.
  • the wicking material is preferably a cotton fiber material, a cellulose material, or other hydrophilic material having pores. It is important in the present application that the material is sufficiently absorbent (i.e., possesses sufficient wicking speed) that the valve closes within a time period that is commensurate with the subsequent withdrawal of the sample diaphragm actuating means described below, so that sample is not subsequently drawn back into the region of the sensor chip.
  • a wash conduit (second conduit) 158 connected at one end to a vent 159 and at the other end to the sample conduit at a point 160 of the sample conduit that is located between vent 157 and sensor chip 153.
  • a fluid is introduced into conduit 158.
  • the fluid is present initially within a foil pouch 161 that is punctured by a pin when an actuating means applies pressure upon the pouch.
  • a short conduit 162 that connects the fluid to conduit 154 via a small opening in the gasket 163.
  • a second capillary stop initially prevents the fluid from reaching capillary stop 160, so that the fluid is retained within conduit 158.
  • a suitable film is obtained by withdrawing fluid by operation of the sample diaphragm 156, until the conductimetric sensor located next to the sensor indicates that bulk fluid is no longer present in that region of conduit 154. It has been found that measurement can be performed at very low (nA) currents, the potential drop that results from increased resistance of a thin film between ground chip and sensor chip (compared to bulk fluid), is not significant.
  • the ground chip 165 is preferably silver/silver chloride. It is advantageous, to avoid air segments, which easily form upon the relatively hydrophobic silver chloride surface, to pattern the ground chip as small regions of silver/silver chloride interspersed with more hydrophilic regions, such as a surface of silicon dioxide.
  • a preferred ground electrode configuration comprises an array of silver/silver chloride squares densely arranged and interspersed with silicon dioxide. There is a further advantage in the avoidance of unintentional segments if the regions of silver/silver chloride are somewhat recessed.
  • Regions R1 - R7 represent specific regions of the conduits associated with specific operational functions.
  • R1 represents the sample chamber;
  • R2 the sample conduit whereby a metered portion of the sample is transferred to the capture region, and in which the sample is optionally amended with a substance coated upon the walls of the conduit;
  • R3 represents the capture region, which houses the conductimetric and analyte sensors;
  • R4 and R5 represent portions of the first conduit that are optionally used for further amendment of fluids with substances coated onto the conduit wall, whereby more complex assay schemes are achieved;
  • R6 represents the portion of the second conduit into which fluid is introduced upon insertion of the cartridge into a reading apparatus;
  • R7 comprises a portion of the conduit located between capillary stops 160 and 166, in which further amendment can occur;
  • R8 represents the portion of conduit 154 located between point 160 and vent 157, and which can further be used to amend liquids contained within.
  • a user places a sample into the cartridge, places the cartridge into the analyzer and in 1 to 20 minutes, a quantitative measurement of one or more analytes is performed.
  • a sequence of events that occur during the analysis is a non-limiting example of a sequence of events that occur during the analysis:
  • an electrical signal 170 representing the position of the electric motor actuating the sample diaphragm 156, the response 171 of the conductimetric electrode, and the electrochemical response 172 of a amperometric immunosensor.
  • the motor depresses the diaphragm, which pushes the sample into the capture region and over the conductimetric sensor.
  • the conductivity rises to a steady value representative of sample filling the portion of the conduit containing the conductimetric sensor.
  • the valve is sealed by contact with the sample.
  • the motor position is stepped back in increments 174, creating a periodic fluctuation in pressure, which draws an air-segmented portion of wash fluid over the sensor. During this period, fluctuations 175 in the immunoassay sensor are seen.
  • the conductimetric response indicates that the wash fluid, which contains substrate, covers the conductimetric sensor. As the fluid is drawn slowly over the sensor, a potential is applied (in this example, every five seconds, for 2.5 second periods) to the sensor, resulting in response 176, which indicates the presence of analyte bound to the sensor.
  • the invention described and disclosed herein has numerous benefits and advantages compared to previous devices. These benefits and advantages include, but are not limited to ease of use, the automation of most if not all steps of the analysis, which eliminates user included error in the analysis.
  • each component printed in the sample holding chamber in the base is shown.
  • the components are BSA, glycine, methoxypolyethylene glycol, sucrose and bromophenol blue (used for quality control - may be viewed by some as a helpful "target").
  • the sample holding chamber in the base has to be corona treated in order to print.
  • the base cocktail is very dilute and won't spread without a corona treatment).
  • the cover is not required to be corona treated although it may be so treated in order to simplify operations. In a preferred embodiment there is no special treatment for the cover and no treatment around the orifice.
  • the print cocktail may be made as follows.
  • An aqueous solution of bromophenol blue is prepared (0.05g in 10g of deionized water).
  • a reagent mixture is prepared by dissolving BSA (0.42g), glycine (2.54g), MePEG (0.39g) and sucrose (1.4g) in 250mL of deionized water.
  • the print cocktail used to print into the cartridge components constitutes reagent mixture (1.2g), bromophenol blue solution (0.23g) mixed with deionized water (53.4g).
EP12179659.3A 2003-09-10 2004-09-09 Dispositif d'immuno-essai possédant une électrode de référence immunologique Active EP2551671B1 (fr)

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US10/658,529 US7723099B2 (en) 2003-09-10 2003-09-10 Immunoassay device with immuno-reference electrode
EP04809719.0A EP1668347B1 (fr) 2003-09-10 2004-09-09 Dispositif d'immuno-essai possedant une electrode de reference immunologique
PCT/US2004/029498 WO2005026689A2 (fr) 2003-09-10 2004-09-09 Dispositif d'immuno-essai possedant une electrode de reference immunologique

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EP04809719.0A Division-Into EP1668347B1 (fr) 2003-09-10 2004-09-09 Dispositif d'immuno-essai possedant une electrode de reference immunologique

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US20100167308A1 (en) 2010-07-01
JP5250007B2 (ja) 2013-07-31
WO2005026689A2 (fr) 2005-03-24
WO2005026689A3 (fr) 2005-08-04
EP2551671A3 (fr) 2013-05-15
US8460922B2 (en) 2013-06-11
CA2878648C (fr) 2017-08-29
US20100203550A1 (en) 2010-08-12
JP5142338B2 (ja) 2013-02-13
CA2973834C (fr) 2021-01-05
US7723099B2 (en) 2010-05-25
WO2005026689A9 (fr) 2005-10-13
JP2011039070A (ja) 2011-02-24
US20100167312A1 (en) 2010-07-01
EP1668347B1 (fr) 2015-07-15
CA2878648A1 (fr) 2005-03-24
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US8808626B2 (en) 2014-08-19
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US8168439B2 (en) 2012-05-01
US20100167386A1 (en) 2010-07-01
JP4891079B2 (ja) 2012-03-07
CA2538826C (fr) 2015-02-24
US20100173396A1 (en) 2010-07-08
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US8309364B2 (en) 2012-11-13
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